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Loss of the E3 ubiquitin ligase MARCHF6 alters hepatic lipid metabolism and drives spontaneous hepatosteatosis

ABSTRACT: Metabolic dysfunction-associated steatotic liver disease (MASLD) and its progressive form, steatohepatitis (MASH), feature excessive hepatic fat accumulation, yet the relative contributions of dietary vs. endogenous fats and their interactions has remained enigmatic. Here, we identify the endoplasmic reticulum–associated E3 ubiquitin ligase MARCHF6 as a pivotal regulator of hepatic lipid metabolism. Global or hepatocyte-specific deletion of Marchf6 induced spontaneous accumulation of triglycerides and cholesteryl esters under chow-fed conditions, revealing a cell-autonomous hepatic defect independent of caloric excess. Mechanistically, loss of MARCHF6 stabilized its substrate squalene epoxidase (SQLE), enhancing sterol pathway flux while concomitantly activating the SREBP1-driven lipogenic transcriptional program and increasing lipoprotein clearance. Accordingly, lipidomic analyses demonstrated remodeling of the hepatic lipidome towards polyunsaturated, long-chain neutral lipids, consistent with increased lipogenesis-driven NADPH consumption. In line with this, pharmacological inhibition of the oxidative pentose phosphate pathway reduced lipid accumulation in MARCHF6-deficient human hepatocytes. Congruently, transcriptomic data from human MASLD/MASH patients revealed reduced hepatic MARCHF6 expression alongside an increase in that of the lipogenic genes SREBF1, FASN, and SCD1. Overall, these data establish MARCHF6 as a multifaceted gatekeeper that integrates sterol turnover, NADPH usage, and lipogenesis to maintain hepatic lipid homeostasis

ORGANISM(S): Mus musculus

PROVIDER: GSE324273 | GEO | 2026/04/25

REPOSITORIES: GEO

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Project description:Fat accumulation, de novo lipogenesis, and glycolysis are key contributors to hepatocyte reprogramming and the pathogenesis of metabolic dysfunction-associated steatotic liver disease (MASLD). The molecular mechanisms affected by steatosis and inflammation in the obese states remain unknown. Here we report that obesity leads to dysregulated expression of protein-tyrosine phosphatases (PTPs) in the liver. Protein Tyrosine Phosphatase Receptor Kappa (PTPRK) was increased in hepatocytes by steatosis and inflammation in humans and mice, and positively correlates with PPARγ-induced lipogenic signalling. Mechanistically, PTPRK-PPARγ upregulation by fat accumulation is dependent upon Notch signalling in mouse primary hepatocytes. PTPRK knockout mice have reduced fat accumulation in adipose tissue and liver after exposure to an obesogenic diet. Phosphoproteomic analysis in isolated hepatocytes and hepatic metabolomics identified specific phosphotyrosine residues in fructose-1,6 bisphosphatase-1 and glycolysis regulation as targets of PTPRK. These changes in glycolysis and de novo lipogenesis revealed PTPRK-dependent metabolic reprogramming in hepatocytes. Moreover, hepatoma cell lines showed reduced colony-forming ability after PTPRK silencing in vitro, and PTPRK knockout mice developed smaller tumours after diethylnitrosamine-induced hepatocarcinogenesis in vivo. Computational modelling identified potential PTPRK inhibitors, which selectively reduced PTPRK activity. The compounds decreased glycolytic rates in hepatoma cell lines, PPARγ expression in primary hepatocytes and steatosis in obese mice. In conclusion, our study defines a novel mechanism for the development of MASLD, revealing a key role of PTPRK on hepatic glycolysis regulation with implications in lipid metabolism, and liver tumour development. We propose PTPRK as a potential target for metabolic liver dysfunction, and the identified inhibitors may represent promising candidates for therapy in obesity-associated liver diseases.

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Loss of the E3 ubiquitin ligase MARCHF6 alters hepatic lipid metabolism and drives spontaneous hepatosteatosis

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